The effects of vitamin D and calcium on primary dysmenorrhea: a systematic review

Dysmenorrhea, affecting approximately 80% of adolescents, significantly impairs quality of life, disrupts sleep patterns, and induces mood changes. Furthermore, its economic impact is substantial, accounting for an estimated $200 billion in the United States and $4.2 million in Japan annually. This review aimed to identify the effects of vitamin D and calcium on primary dysmenorrhea. We conducted a comprehensive literature search across Web of Science, PubMed, Scopus, and Science Direct, focusing on studies published from 2010 to 2020. Keywords included 'primary dysmenorrhea', 'vitamin D', '25-OH vitamin D3', 'cholecalciferol', and 'calcium'. The quality assessment of the articles was done using the Consolidated Standards of Reporting Trials (CONSORT) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklists, and the risk bias was assessed using the Cochrane assessment tool. Abnormal low Vit. D levels increased the severity of primary dysmenorrhea through increased prostaglandins and decreased calcium absorption. Vitamin D and calcium supplements could reduce the severity of primary dysmenorrhea and the need for analgesics. This systematic review found an inverse relation between the severity of dysmenorrhea and low serum Vit. D and calcium.. Vitamin D and calcium supplements could reduce the severity of primary dysmenorrhea and the need for analgesics.

The usual treatment of dysmenorrhea includes non-steroidal anti-inflammatory drugs (NSAIDs) and oral contraceptives [13,14].While NSAIDs decrease the severity of dysmenorrhea by inhibiting PGD synthesis, they increase the risk of gastrointestinal bleeding and gastric ulcers [15,16].There is little evidence JOURNAL of MEDICINE and LIFE.VOL: 16 ISSUE: 11 NOVEMBER 2023 Licensed under CC BY 4.0 regarding the efficacy of oral contraceptives in the treatment of dysmenorrhea, and 50% of women stopped oral contraceptives prescribed for the treatment of their dysmenorrhea because of their side effects [17].
The treatment of dysmenorrhea with therapeutic options other than NSAIDs and oral contraceptives could be helpful and limit the use of NSAIDs and oral contraceptives.Understanding the presence of vitamin D receptor in the uterus and ovaries [18] highlights the role of Vit.D in regulating inflammatory cytokines [19].Vit.D metabolites could reduce the level of inflammatory cytokines [20,21].Inverse relationships between the severity of dysmenorrhea and serum Vit.D and calcium (Ca) were reported in a systematic review [11].In addition, Karacin et al. [22] found a significant negative association between dysmenorrhea and Vit.D. Kucukceran et al. [23] reported a significant reduction in menstrual pain and consumed NSAIDs after a single dose of oral cholecalciferol compared to placebo.A randomized trial reported reduced severity of dysmenorrhea after Vit.D intake [8] and Zarei et al. [24] reported a significant reduction in menstrual pain after Ca intake.Consequently, this review aimed to assess the impact of Vit.D and Ca on primary dysmenorrhea.

MATERIAL AND METHODS
A comprehensive search was conducted across Web of Science, PubMed, Scopus, and Science Direct, focusing on articles/ studies published between 2010 and 2020 containing keywords such as "primary dysmenorrhea", "painful menses", and "Vit.D", "Vit.D3", "25-OH Vit.D3", or "cholecalciferol", and "Ca".The objective was to assess the impact of Vit.D and Ca in alleviating the severity of primary dysmenorrhea.

Inclusion and exclusion criteria
Studies examining vitamin D and/or calcium in primary dysmenorrhea involving non-smoking, non-alcoholic women of reproductive age with regular menses and low serum vitamin D levels and studies that included participants without a history of uterine disorders (i.e., fibroids, adenomyosis, endometrial hyperplasia or endometrial polyps) or ovarian disorders (ovarian cysts, endometriosis, or polycystic ovaries) were included in this systematic review.
Studies that included pregnant women, women with medical disorders (i.e., gastrointestinal, renal, or cardiac disorders), uterine (i.e., fibroids, adenomyosis, endometrial hyperplasia or endometrial polyps), ovarian disorders (ovarian cysts, endometriosis, or polycystic ovaries), women with previous pelvic surgery, psychological or neurological disorders, or who received hormonal therapy were excluded from this systematic review.

Study selection
Five hundred sixty articles were initially retrieved.Eligible articles were evaluated by two independent authors (AD and IA).After reviewing the titles and abstracts of each article, 535 articles were not eligible for inclusion in this systematic review because of the above-mentioned exclusion criteria (Figure 1).After a full review (i.e., including the results and discussions) of the remaining 25 articles, another 8 articles were excluded (published before 2010, irrelevant or duplicate), and finally, 17 articles were eligible and included in this systematic review (Figure 1).

Quality assessment
The quality assessment of the articles was done using the Consolidated Standards of Reporting Trials (CONSORT) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklists.CONSORT is a 25-item checklist focusing on the article design, analysis, and interpretation.STROBE is a 22-item checklist evaluating different sections of the observational studies [11].

Risk bias assessment
The risk bias was assessed by two independent authors (AD and IA) using the Cochrane risk-bias assessment tool, which includes selection bias, performance bias, detection bias, attrition bias, and reporting bias.

Data extraction
The following data were extracted: name of the first author, country, publication year, study design and sample size, age of participants and their age of menarche, body mass index (BMI), duration and severity of dysmenorrhea, intervention, serum Vit.D, dysmenorrhea assessment tool (i.e., visual analog scale [VAS] or numeric rating scale [NRS], or verbal intensity pain scale [VIPS]) and results.

Vitamin D and severity of dysmenorrhea
Although two studies did not find a significant relationship between serum Vit.D levels and the severity of primary dysmenorrhea [25,27], an inverse association between serum Vit.D and the severity of primary dysmenorrhea was observed in two other studies.These studies reported that individuals with lower serum Vit.D levels experienced more severe primary dysmenorrhea symptoms [22,26].

Effectiveness of vitamin D and calcium in reducing the severity of dysmenorrhea
Clinical studies reported that vitamin D supplementation decreased the severity of dysmenorrhea [25, 32-34, 36, 37].A comparative study [30,31] found vitamin D more effective than vitamin E or ginger in reducing severe dysmenorrhea symptoms.Participants receiving Vit.D supplements exhibited a higher recovery rate from primary dysmenorrhea and consumed fewer NSAIDs [32].Zarei et al. [24] found that calcium intake was more effective than Vit.D and Ca combined in relieving severe

Dysmenorrhea-related symptoms
The effect of Vit.D and Ca supplements on the dysmenorrhea-related symptoms were mentioned in five of the reviewed studies [22,25,27,28,30].Participants with low serum Vit.D were at greater risk of dysmenorrhea-related symptoms, including headache, fatigue, depression, mood swings, breast tenderness, nausea, and vomiting in two studies [22,27].Furthermore, Vit.D intake (high doses) decreased the severity of dysmenorrhea dysmenorrhea.Charandabi et al. [33] found that Ca alone or combined with magnesium was equally effective in reducing the severity of dysmenorrhea.Furthermore, Mehrpooya et al. [32] reported that omega-3 effectively reduced the pain of primary dysmenorrhea.Table 1 shows the reviewed articles.

Interventions/treatment and duration
The forms of vitamin D used in the clinical studies included in this review were drops or capsules of 100 mg, 667 IU, 50,000 IU, or 300,000 IU.Calcium was used in the form of capsules in clinical studies included in this review.The intervention/treatment duration varied across studies, ranging from 4 to 12 weeks.

The parathyroid hormone and other biochemical markers in dysmenorrhea
Serum Ca and parathyroid hormone (PTH) were evaluated in four studies [22,23,27,33].One study reported significantly lower serum Ca levels and higher PTH levels in the primary dysmenorrhea group compared to controls.In another study, serum Ca and PTH levels were measured in three groups categorized by Vit.D status (insufficient Vit.D (21-29 ng/mL), deficient Vit.D (10-20 ng/mL), and severely deficient Vit.D  Calcium intake reduces the severity of menstrual cramps and backaches [44].One study found that menstrual cramps and back pain were reduced after 1,200 mg of Ca per day for three months [40].Low serum Ca increases uterine cramps and the severity of primary dysmenorrhea [22], which explains the role of Ca in regulating uterine muscle contractions [45].
This systematic review found that Vit.D intake in any dose could effectively reduce the severity of primary dysmenorrhea, and the intake of 50,000 IU of Vit.D weekly is recommended to treat Vit.D deficiency.Vit.D intake may also reduce the risk of PMS, possibly due to the regulation of Ca absorption and inflammatory cytokines [46,47].
Vit. D changes were also reported with estradiol changes during different phases of the ovulatory and menstrual cycles [39].A single oral dose (300,000 U) of cholecalciferol for five days before the menstrual flow reduces the severity of primary dysmenorrhea [35].Vit.D decreases the severity of dysmenorrhea through decreased expression of cyclooxygenase 2 and inhibition of PGD production [48].
This systematic review found a significant positive relationship between the severity of dysmenorrhea and PTH, explained by the role of PTH in renal reabsorption and intestinal absorption of Ca.
The role of Ca in muscle contraction and relaxation was explained previously [47,48], and the three hormones, calcitonin, PTH, and 25-hydroxy Vit.D (which regulates serum Ca) may play a physiological role in dysmenorrhea [49].Low Vit.D is often associated with low serum Ca due to decreased intestinal Ca absorption.Low serum Ca increases PTH secretion with a subsequent increase in the renal reabsorption and intestinal absorption of Ca [48].
No significant relationship between serum phosphorus and primary dysmenorrhea was found in this systematic review, which needs to be confirmed in future studies.However, we found a significant relationship between the severity of dysmenorrhea-related symptoms and both serum Vit.D and Ca.Additionally, this review found that Vit.D and Ca supplements could reduce primary dysmenorrhea and the consumed analgesics.
[46] and Baird et al. [50] reported an inverse relationship between serum Vit.D and the risk of dysmenorrhea and mood changes.Rahnemaie et al. [25], found that serum levels of Vit.D was inversely related to the severity of dysmenorrhea-associated symptoms, including fatigue, headache, nausea, and vomiting.
Research on the impact of fish oil on primary dysmenorrhea is limited [51].However, a study by Zamani et al. [52] indicated that fish oil intake can reduce the severity of primary dysmenorrhea.This effect is likely due to the ability of fish oil to inhibit the production of PGDs and leukotrienes, which are known to contribute to menstrual pain.Vitamin E and omega-3 intake have been observed to lessen the severity of dysmenorrhea.This reduction in pain severity may be attributed to the stimulating effect of vitamin E on beta-endorphins, which are natural pain-relieving compounds in the body [53].
Daily et al. [54] found that vitamin D, E, and ginger effectively decreased the severity of dysmenorrhea (the effect was more favorable in the ginger group than in the vitamin D and E groups).Rahnama et al. [11] suggested that ginger contents (i.e., gingerol and gingerdione) may have analgesic and anti-inflammatory effects [55].Further, in-vitro studies support this by showing that and dysmenorrhea-related symptoms (i.e., backache and crying tendency) [28].In addition, Mehrpooya et al. [32] reported that omega-3 supplementation reduced vomiting and breast tenderness, while calcium intake alleviated bloating symptoms.
Abnormal low serum vitamin D can aggravate the symptoms associated with dysmenorrhea, while Vit.D and Ca intake could improve those symptoms.Low serum vitamin D could increase the severity of primary dysmenorrhea through increased PGD synthesis and decreased intestinal Ca absorption.At the same time, low serum Ca could increase the amplitude of uterine muscle contractility with subsequent uterine muscle ischemia and pain.Consequently, supplementation with Vit.D and Ca may effectively reduce the severity of primary dysmenorrhea and the need for pain-relief medications like NSAIDs.

DISCUSSION
A comprehensive search was conducted across Web of Science, PubMed, Scopus, and ScienceDirect to retrieve articles and studies published between 2010 and 2020.The search criteria included the following keywords: 1) 'primary dysmenorrhea' or 'painful menses', 2) 'vitamin D', 'vitamin D3', '25-OH vitamin D3', or 'cholecalciferol', 3) 'calcium', with the aim of evaluating the role of vitamin D and calcium in reducing the severity of primary dysmenorrhea.Five hundred sixty articles were initially retrieved.Eligible articles were evaluated by two independent authors (AD and IA).After reviewing the titles and abstracts of each article, 535 of them were not eligible for inclusion in this systematic review (because of the above-mentioned exclusion criteria).After a full review (i.e., including the results and discussions) of the remaining 25 articles, another eight were excluded (published before 2010, irrelevant or duplicate), and finally, 17 were eligible and were included in this systematic review.
A significant relationship between dysmenorrhea and serum Ca was reported by Zarei et al. [24].Impaired Ca regulation is one of the factors contributing to the increased severity of dysmenorrhea [39].Low serum Ca was also reported in women with premenstrual syndrome (PMS), which supports the role of Ca in neuromuscular regulation [39].Low serum Ca could increase the amplitude of uterine muscle contraction with subsequent uterine muscle ischemia and pain [40].The relationship between dysmenorrhea and serum Ca needs further studies.
An inverse relation between the severity of dysmenorrhea and serum Vit.D was reported in Karacin et al. [22] and Abdul-Razzak et al. [27] studies.Thys-Jacobs [39] also reported Vit.D deficiency in women with dysmenorrhea.Low serum Vit.D increases the severity of primary dysmenorrhea through increased PGD synthesis and decreased intestinal Ca absorption.In addition, it plays a crucial role in Ca absorption and metabolism (stages of hydroxylation) [41].
VDR expression in the uterus and ovaries [18] explains the role of Vit.D in inflammatory cytokine regulation [19].Vit.D metabolites could reduce the level of inflammatory cytokines [20,21,42].Vitamins, minerals absorption, and metabolism could be important in treating menstrual problems [42].
Abdul-Razzak et al. [27] and Anagnostis et al. [43] reported an association between severe dysmenorrhea and serum Vit.D and Ca in adolescents.
In addition, a nutritional balance could improve menstrual disorders and dysmenorrhea.Thys-Jacobs [39] reported a close ginger can inhibit the production of PGDs and leukotrienes, which are known to exacerbate menstrual pain [29].The limited number of research investigating the effects of vitamin D and calcium on the severity of dysmenorrhea was the only limitation of this study, and further studies in this area are warranted.

CONCLUSION
This systematic review found an inverse relationship between the severity of dysmenorrhea and low serum levels of vitamin D and calcium.The findings suggest that supplementation with vitamin D and calcium could effectively reduce the severity of primary dysmenorrhea and the reliance on analgesics.

Table 1 . Characteristics of the articles included in the systematic review
3. Calcium (Ca).
JOURNAL of MEDICINE and LIFE.VOL: 16 ISSUE: 11 NOVEMBER 2023 Licensed under CC BY 4.0 JOURNAL of MEDICINE and LIFE.VOL: 16 ISSUE: 11 NOVEMBER 2023 Licensed under CC BY 4.0

Table 1 . Continued. Characteristics of the articles included in the systematic review
JOURNAL of MEDICINE and LIFE.VOL: 16 ISSUE: 11 NOVEMBER 2023 Licensed under CC BY 4.0 S BMI: Body mass index.Ca: Calcium.Mg: Magnesium.IU: International unit.NM: Not mentioned.NRS: numeric rating scale.NS: Non-significant.RCT: Randomized controlled trial.S: Significant.VAS: Visual analogue scale.VIPS: verbal intensity pain scale.Vit.D: Vitamin D. Vit.E: Vitamin E.

Table 1 . Continued. Characteristics of the articles included in the systematic review JOURNAL
of MEDICINE and LIFE.VOL: 16 ISSUE: 11 NOVEMBER 2023 Licensed under CC BY 4.0 relationship between Ca supplements and reduced severity of dysmenorrhea.